3-(ortho-chloro-phenyl)-2-(pyridyl)-acrylonitriles



United States Patent 0 3,8545% fi-(QRTEEGCHLGRG-PHENYL =2-(PYREDYL3- ACRYLGNHRKLES William Lassie lioness, New Providence, NJ, assignor to Cilia Corporation, a corporation of Delaware No Brewing. lFiied duly 26, E61, 822'. No. 126,887 2 Claims. (Ci. ass-2am The present invention concerns nitrile compounds. More especially, it relates to 3-(o-halogeno-phenyl)-2- (pyridyD-"ropionitriles of the formula and 3- (o-halogeno-phenyl)-2- (pyridyl) -acrylonitriles of the formula oN R Py t=i l Hal in which iy represents pyridyl, R represents hydrogen or lower alkyl, and Hal stands for halcgeno, salts, N-oxides, salts of N-oxides and quaternary ammonium compounds thereof, as well as process for the preparation of these compounds.

The pyridyl ra ical Py represents primarily 3-pyridyl, as well as 2-pyridyl or 4-pyridyl, as well as substituted pyridyl, such as lower alkyl-pyridyl, in which lower alkyl has from one to four carbon atoms, e.g., methyl, ethyl, n-propyl, isoproopyl, nbutyl and the like, lower alkoxy-pyridyl, in which lower alkoxy has from one to four carbon atoms, e.g., methoxy, ethoxy, isopropyloxy, n-butyloxy and the like, halogeno-pyridyl, in which halogeno has an atomic weight between 19 and 80, e.g., fiuoro, chloro or brorno.

The group R stands primarily for hydrogen, but may also represent lower alkyl having from one to four carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl and the like.

The group Hal represents halogeno, and stands primarily for halogeno having an atomic weight between 19 and 8t), e.g., fiuoro, chloro or bromo.

Salts of the compounds of this invention are particularly pharmacologically or therapeutically acceptable, non-toxic acid addition salts with inorganic acids, e.g., hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like, or with organic acids, such as organic carboxylic acids, e.g., acetic, propionic, glycolic, lactic, pyrnvic, oxalic, malonic, succinic, maleic, hydroxymaleic, dihydroxymaleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, Z-acetoxybenzoic, acid and the like, or with organic sulfonic acids, e.g., methane sulfonic, ethane sulfonic, Z-hydroxyethane sulfonic, benzene sulfonic, toluene sulfonic acid and the like. Salts which are primarily used for identification purposes are particularly those with acidic organic nitro compounds, e.g., picric, picrolonic, flavianic acid and the like, or with metal complex acids, e.g., phosphotungstic, phosphomolybdic, chloroplatinic, Rein cke acid and the like.

Quaternary ammonium derivatives of the compounds of this invention are particularly those with reactive esters formed by alcohols with strong acids, particularly the quaternary ammonium compounds with lower alkyl halides, e.g., methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, phenyl-lower alkyl halides, e.g., benzyl, l-phenylethyl or 2-phenylethy1 chloride, bromide or iodide and the like, lower alkyl sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, lower alkyl lower alkane sulionates, e.g., methyl or ethyl methane or "ice ethane sulr'onate and the like, or lower alkyl monocyclic carbocyclic aryl sulfonates, e.g., methyl p-toluene sulronate and the like. Also included as quaternary ammonium compounds are the quaternary ammonium hydroxides, and the salts resulting from the reaction of such quaternary ammonium hydroxides with inorganic or organic acids, such as with those described hereinbefore as being suitable for the preparation of acid addition salts.

N-oxides and salts or" N-oxides with acids, such as the pharmacologically or therapeutically acceptable, non-toxic acid addition salts with the acids mentioned hereinbefore, are also included within the scope of the invention.

T he compounds of the present invention may be in the form of mixture of isomers (e.g., racemates and the like) or or" single isomers.

The compounds of this invention inhibit certain functions of the adrenal cortex. Known adrenal cortical inhibitors, which cause a decrease in the secretion of corticoid steroids, as, for example, 1,2-bis-(3-pyridyl) -2-methyll-propanone, exhibit a decrease in the secretion of hydrocortisone (Compound F) and corticosterone (Compound B), which decreases are accompanied by a marked increase in the secretion of l1-d6SOXY-17zx-hYdIOXY-C0tticosterone (Compound S); others show a decrease of the secretion of hydrocortisone (Compound F), ll-desoxy- -'7a-hydroxy-corticosterone (Compound S) and aldosterone, but cause an increase in the secretion of corticosterone (Compound B). Furthermore, other known adrenal cortex inhibitors, such as, for example, 3,3-di-(4- aminophenyl)-2-butanone, although they show a decrease in the secretion of hydrocortisone (Compound F), corticosterone (Compound B) and 11-desoxy-17a-hydroxycorcosterone (Compound S), are usually accompanied by numerous side-effects, such as progestational proper ties, anesthetic and hypothermic activities, inhibition of the functioning of the thyroid gland, liver hypertrophy and the like.

It has now been found that the 3-(o-hal0geno-phenyl)- Z-pyridyl-propionitriles of this invention exhibit a marked decrease of the secretion of hydrocortisone (Compound F), corticosterone (Compound B), and 11-des0Xy-17ahydroxy-corticosterone (Compound S); on the basis of these results, it appears that these compounds are inhibitors of the llfi-hydroxylase and the 17a-hydroxylase enzyme systems. The previously-described 3-(o-halogeno-phenyl)-2-pyridyl-acrylonitrile compounds show a somewhat different effect on the adrenal cortex; they cause a decrease of the secretion of hydrocortisone (Compound F) and an increase of the secretion of corticosterone (Compound B), while that of 1l-desoxy-l7a-hydroXy-corticosterone (Compound S) remains unchanged. In addition, the compounds of this invention are remarkably free from any other pharmacological activities of any undesired sideefiects characteristic of certain adrenal cortex inhibitors.

The compounds of the present invention, possessing specific adrenal cortical inhibitory activity, can, therefore, be used as diagnostic tools for the determination of dysfunction of the pituitary gland, or as agents in the treatment of conditions due to adrenal cortical hyperfunction, e.g., Cushings syndrome, primary aldosteronisrn, secondary aldosteronism, and the like. Furthermore,

the preferential inhibition of certain hydroxylases, such as the llfl-hydroxylase enzyme system or the l7a-hydroxylase enzyme systems, makes the compounds of this invention useful as aids in the study of the biosynthetic pathways of corticoid hormone formation. It has also been determined by Way of tests in dogs, that the com pounds of this invention show oral activity.

The compounds of this invention may be used in the form of pharmaceutical preparations, which contain the pharmacologically active compounds in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral or parenteral administration. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, ,magnesium stearate, talc, vegetable oils, benzyl alcohols, ,stearyl alcohol, gums, propylene glycol, polyalkylene glycols or any other known carrier used for pharmaceutical preparations. The latter may be in solid form, for example, as capsules, tablets, dragees and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers, etc. They may also contain, in combination, other useful substances.

7. The 3-(o-halogeno-phenyl)-2-(pyridyl)-propionitriles of the formula 7 ON R in which Py, R and Hal have the previously-given meanin which R and Hal have the previously-given meaning, and, if desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, converting a resulting compound into a salt, a quaternary ammonium derivative, an N-oxide or a salt of an N-oxide thereof, and/or, if desired, separating a mixture of .isomers into the single isomers. The above reaction is carried out according to known methods; for example, an alkali metal, e.g., lithium, sodium, potassium and the like, salt of a (pyridyl)-acetonitrile (prepared, for example, by treating the latter with an alkali metal, e.g., lithium, sodium, potassium and the like, with an alkali metal hydride or amide, e.g., lithium, sodium or potassium hydride or amide and the like, or with analkali metal lower alkanolate, e.g., sodium or potassium methanolate or ethanol-ate and the like, in a suitable solvent), isreacted with a compound of the formula V o-HalC H CH(R)l-Ial (representing the reactive ester of a compound of the formula o-HalC ,-H CH(R)-OH), in which Hal has the previously-given meaning and Hal represents halogeno, particularly chloro, bromo or iodo, or with a compound of the formula o -Hal-C H CH(R)O--SO R (representing the reactive ester of a compound of the formula o-HalC H CI-I(R)-OH with an organic 'sulfonic acid), in which Hal has the previously-given meaning, and R stands for an aromatic radical, such as lower alkyl, e.g., methyl, ethyl and the like, or monocyclic carbocyclic aryl, e.g., p-tolyl and the like. The reaction 'is carried out in the presence of a suitable inert reagent, e.g., N,N-dimethylformamide, benzene, toluene, p-dioxane and the like, if necessary, while cooling or at an elevated temperature, in a closed vessel and/ or in the atmosphere of an inert gas, e.g. nitrogen and the like. i

The 3 (o-halogeno-phenyl)-2-(pyridyl)-propionitrile compounds of the above formula may also be prepared, for example, by converting in a compound of the formula Iiial 4 group R into a cyano group, and, if desired, carrying out the optional steps.

A group R, capable of being converted into a cyano group, is particularly a reactive esterified hydroxyl group, particularly a halogeno atom (representing a hydroxyl group esterified with a hydrohalic acid), e.g., chloro, bromo and the like. The conversion of such group into a cyano group is preferably carried out by treatment with a metal, particularly an alkali metal cyanide, e.g., potassium cyanide and the like. The reaction is carried out according to known methods, for example, in the presence of a suitable solvent or solvent mixture, e.g., aqueous ethanol, dimethylsulfoxide and the like, if necessary, while cooling or at an elevated temperature, in a closed vessel, and/or in the atmosphere of an inert gas, e.g., nitrogen and the like.

3(o-halogeno-phenyl)-2-(pyridyl)-acrylonitrile pounds having the formula l He! in which Py and Hal have the previously-given meaning, salts, quaternary ammonium compounds, N-oxides or salts of N-oxides thereof, may be prepared, for example, by treating a pyridyl-acetonitrile of the formula in which Py has the previously-given meaning, with an o-halogen-benzaldehyde, of the formula in which Hal has the previously-given meaning, and, if desired, carrying out the optional steps.

The above reaction is carried out according to known methods; preferably, it is performed in the presence of a basic reagent, such as, for example, an alkali metal lower alkanolate, e.g., lithium, sodium or potassium methanolate, ethanolate, n-butanolate, tert. butanolate and the like, a strong quaternary ammonium hydroxide, e.g.,

I I V Iifal in which Py, R and Hal have the previously-given meaning, salts, quaternary ammonium compounds, N-oxides or salts of N-oxides, may also be prepared, for example, by introducing a halogeno atom into the aliphatic portion of one of the previously-described 3-(o-halogeno-phenyD-2- (pyridyl)-propionitrile compounds having the formula CN B.

1 Hal in which Py, R and Hal have the previously-given meaning, or a salt or another derivative thereof, and splitting off hydrogen halide, and, if desired, carrying out the optional steps.

A halogeno atom may be introduced into the aliphatic portion of a 3-(o-halogeno-phenyl)-2-(pyridyl)-propionitrile, or a derivative, such as a salt thereof, by treatment with halogen, e.g., chlorine, bromine and the like, according to knownmethods, preferably in the presence of light and/or at an elevated temperature. Dehydrohalogenation to introduce the desired double bond is per-- also,

formed according to known methods, for example, by heating the halogenated compound or by treatment with suitable reagents, such as, for example, pyridine hydrochloride, barium oxide, calcium oxide or any other known dehydrohalogenating reagent.

The 3-(o-halogeno-phenyl) 2 (PYridyl)-acrylonitriles having the previously-shown formula may also serve as starting materials for the preparation of the 3-(o-halogeno-phenyl)-2-(pyridyl)-propionitriles having the above formula; the latter may be obtained by removing in a 3- (o-halogeno-phenyl)-2-(pyridyl)-acrylonitrile having the formula GN R I ial in which Py, R and Hal have the above-given meaning, or a salt thereof, the carbon-carbon double bond of the acry lonitrile portion, and, if desired, carrying out the optional steps.

The removal of the carbon-carbon double bond in the acrylonitrile portion is carried out according to known reduction procedures, for example, by treatment with catalytically activated hydrogen, e.g., controlled hydrogenation at atmospheric pressure in the presence of a suitable catalyst, e.g., palladium on charcoal, Raney nickel and the like, and of an appropriate solvent, e.g. ethanol, acetic acid and the like.

The 3-(o-halogeno-phenyl)- 2 -(pyridyl)-propionitriles and 3-(o-halogeno-phenyl)-2-(pyridyl)-acrylonitriles of this invention may also be formed, for example, by converting in a 3-phenyl-2- (pyridyl)-propionitrile of the formula CN P.

or in a 3-phenyl-2-(pyridyl)-acryonitrile of the formula CN B in which formulae Py and R have the previously-given meaning, and R represents a substituent capable of being converted into a halogeno atom, or a erivative of such compound, the group R into a halogeno atom, and, if desired, carrying out the optional steps.

The group R to be replaced by halogeno, is, for example, an amino group, which may be converted into a halogeno atom according to the Sandmeyer reaction, i.e., diazotization of the 3-(o-amino-phenyl)-2-(pyridyl)- propionitrile or the 3-(o-amino-phenyl)-2-(pyridyD-acr lonitrile (for example, treatment with sodium nitrite in the presence of hydrochloric acid) and decomposition of the resulting diazonium salt with a suitable halide salt (for example, a cuprous halide, e.g., cuprous chloride, cuprous bromide and the like, or potassium iodide and the like).

A salt resulting from one of the above procedures may be converted into the free base according to known methods, for example, by treatment with an alkali reagent, such as an alkali metal hydroxide, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, an alkali metal carbonate, e.g., sodium or potassium carbonate or hydrogen carbonate and the like, ammonia, or any other suitable reagent, such as an anion exchange resin and the like.

A resulting base may be converted into a salt thereof according to known methods, for example, by treating a solution of the base in an enert solvent or solvent mixture with the appropriate acid, such as one of the above-mentioned inorganic or organic acids, if desired,

a solution thereof in an inert solvent or solvent mixture, and isolating the desired salt. A resulting salt may be converted into another salt, for example, by reacting the former with an inorganic salt of an inorganic or organic acid, such a an alkali metal, e.g., sodium and the like, salt of such acid. Salts may be isolated in the form of hydrates.

The quaternary ammonium derivatives of the compounds of this invention may be obtained, for example, by reacting the base with an ester formed by an alcohol and a strong inorganic, such as a hydrohalic, acid, e.g., hydrochloric, hydrobromic, hydriodic acid and the like, or sulfuric acid, etc., or a strong organic acid, particularly an organic sulfonic acid, e.g., p-toluene sulfonic acid and the like, particularly with one of the previouslymentioned reactive esters. The quaternizing reactions may be performed in the presence or absence of a solvent, while cooling, at room temperature or at an elevated temperature, at atmospheric pressure or in a closed vessel under pressure, and, if desired, in the atmosphere of an inert gas, e.g., nitrogen and the like.

Quaternary ammonium compounds obtained may be converted into the corresponding quaternary ammonium hydroxides, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with an anion exchanger, or by electrodialysis, etc. From a resulting quaternary ammonium base there may be prepared quaternary ammonium salts by treatment with acids, such as, with those outlined hereinbefore for the preparation of the acid addition salts or with mono-lower alkyl sulfates, e.g. methyl sulfate, ethyl sulfate and the like. A quar ternary ammonium compound may also be converted directly into another quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride to yield the quaternary ammonium chloride, or a quaternary ammonium iodide may be converted into the corresponding chloride by treatment with hydrochloric acid in anhydrous methanol. Quaternary ammonium compounds may also be isolated in the form of hydrates.

N-oxides of the compounds of this invention may be prepared according to known methods, for example, by reacting the free base with a suitable Noxidizing reagent, such as, for example, hydrogen peroxide or a per-acid, e.g., persulfuric, peracetic, perbenzoic, monoperphthalic acid and the like, preferably in the presence of a suitable solvent. A resulting N-oxide may be converted into an acid addition salt thereof by treatment with an acid according to the previously-mentioned procedure.

Resulting mixtures of isomers may be converted into the single isomers according to known methods. For example, racemates may be resolved into the optically active dand l-forms, for example, by treating a racemic mixture, preferably in solution with an inert solvent or solvent mixture, with one of the optically active forms of an acid containing an asymmetric carbon atom, or a solution thereof, and isolating the resulting salt. Especially useful as optically active forms of salt-forming acids having an asymmetric carbon atom are D-tartaric (l-tartaric) acid of L-tartaric (d-tartaric) acid; the optically active forms of malic, mandelic, camphor-IO- sulfonic, quinic acid and the like, may also be used. A resulting salt may be converted into the free and optically active base according to process as outlined hereinbefore, and an optically active base may be converted into an acid addition salt, a quaternary ammonium compound, an N-oxide or a salt of an N-oxide thereof according to the previously-mentioned methods.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any state of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.

In the process of this invention such starting materials 1 Example 1 A total of 5.0 g. of a 53 percent sodium hydride suspension in mineral oil is added in portions to an icewater cooled solution of 11.8 g. of 3-pyridyl-acetonitrile inv 75 ml. of N,N-dimethylformamide while stirring. After the hydrogen evolution has ceased, a solution of 16.1 g. of o-chloro-benzyl chloride in 50 ml. of benzene is added dropwise to the clear red solution of the sodium salt of the 3-pyridyl-acetonitrile. Cooling is discontinued, and the reaction mixture is stirred for an additional hour and then allowed to stand at room temperature for 15 hours. The inorganic precipitate is filtered off, the filtrate is concentrated to about 30 ml. under reduced pressure and Water is added. The organic material is extracted with diethyl ether, the ether solution is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. The remaining red, viscous oil is distilled; the fraction boiling between the range of 130- 165/ 0.03 mm. is collected (11.6 g.) and is dissolved in 100 ml. of 1 N aqueous hydrochloric acid. The acid solution is washed once with diethyl ether and once with hexane to remove all non-basic organic materials, and the acidic solution is made basic with solid sodium carbonate. The organic material is extracted with diethyl ether, the ether solution is worked up as shown hereinbefore to yield 8.1 g. of 3-(o-chloro-phenyl)-2-(3- pyridyl)-propionitrile of the formula (3 pyridy1)-propionitrile, 3-(o-bromo-phenyl)-2-(3-pyridyl)-propionitrile, 3 (o-chloro-phenyl)-2-(2-pyridyl)- propionitrile, 3 (o-chloro-phenyl)-2-(4-pyridyl)-propionitrile, (3- (o-chloro-phenyl)-2- 3-pyridyl) -butyronitrile, 3 (o chloro phenyl) 4 methyl-2-(3-pyridyl)-valeronitrile and the like.

Example 2 A solution of 2.56 g. of 3-pyridyl-acet0nitrile and 3.0 g. of o-chloro-benzaldehyde in 13 ml. of ethanol (95 pero cent) is stirred at room temperature while adding drop- Wise 0.8 ml. of a 2 N solution of sodium ethanolate in absolute ethanol. A crystalline material i formed; water is added, and the solid material is filtered off and Washed with a lzl-mixture of ethanol and water. The desired 3- (o-chlorophenyl) -2-(3-pyridyl)-acrylonitrile of the formula is recrystallized from an ethanol-water mixture and melts at 117118 (total yield: 5.1 g.).

Other 3- (o-halogeno-phenyl -2- (pyridyl -acrylonitrile, 3 (o-bromo-phenyl)-2-(3-pyridyl)acrylonitrile, 3 (ofluoro-phenyl)-2-(Z-pyridyl)-acrylonitrile, 3 (o chlorophenyl)-2-(4-pyridyl)-acrylonitrile and the like, may be prepared according to the above procedure.

What is claimed is: a 1. A member selected from the group consisting of a compound of the formula References Cited by the Examiner UNITED STATES PATENTS 2,507,631 5/60 Hartmann et a1 260-294.9 2,727,895 12/55 Sperber et a1 260294.9 2,898,338 8/59 Villani 260-294.9

FOREIGN PATENTS 286,343 2/ 5 3 Switzerland.

OTHER REFERENCES Castle et al., J. Org. Chem., vol. 20, pp. 9879 (1955). Buu-Hoi et al., J. Org. Chem., vol. 20, pp. 1407-11 (1955).

Herz and Murty, J. Org. Chem., vol. 26, pp. 41822 (1961).

IRVING MARCUS, Primary Examiner.

DUVAL T. MCCUTCHEN, JOHN D. RANDOLPH, NICHOLAS S. RIZZO, WALTER A. MODANCE,

Examiners. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 